Anticholinergic Drugs and Amantadine in the Treatment of Parkinson’s Disease

  • A. E. Lang
  • R. D. G. Blair
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 88)


Anticholinergics and amantadine both result in mild to moderate improvement in Parkinson’s disease. These drugs still have an important role to play in the treatment of the disease despite the greater clinical effects of levodopa and dopamine agonists. They may be used either as monotherapy or as adjunctive treatment. Benefit can be obtained in all stages of the disease, but it is typically most noticeable early on when disability is less marked. Many neurologists utilize these drugs initially in hopes of delaying the need for levodopa and later to permit the use of lower doses of this agent because of increasing concern that early treatment with levodopa may create many of the long-term problems faced in the later stages of the disease. In this chapter we will review anticholinergic and amantadine treatment of Parkinson’s disease, emphasizing the proposed mechanisms of action, what is known of the pharmacokinetics, the clinical effectiveness and side effects.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Ahmed A, Marshall PB (1962) Relationship between antiacetylcholine and antitremorine activity in antiparkinsonian and related drugs. Br J Pharmacol Chemother 18: 247–257PubMedGoogle Scholar
  2. Allen RM (1983) Role of amantadine in the management of neuroleptic induced extrapyramidal syndromes: overview and pharmacology. Clin Neuropharmacol 6 (Suppl 1): S64–S73PubMedCrossRefGoogle Scholar
  3. Appleton DB, Eadie MJ, Sutherland JM (1970) Amantadine hydrochloride in the treatment of parkinsonism. Med J Aust 2: 626–629PubMedGoogle Scholar
  4. Bailey EV, Stone TW (1975) The mechanism of action of amantadine in parkinsonism: a review. Arch Int Pharmacodyn Ther 216: 246–262PubMedGoogle Scholar
  5. Barbeau A, Mars H, Botez MI, Joubert M (1971) Amantadine-HCl (Symmetrel) in the management of Parkinson’s disease: a double-blind cross-over study. Can Med Assoc J 105: 42–46PubMedGoogle Scholar
  6. Bauer RB, McHenry JT (1974) Comparison of amantadine, placebo and levodopa in Parkinson’s disease. Neurology (NY) 24: 715–720Google Scholar
  7. Birket-Smith E (1974) Abnormal involuntary movements induced by anticholinergic therapy. Acta Neurol Scand 50: 801–811PubMedCrossRefGoogle Scholar
  8. Birket-Smith E (1975) Abnormal involuntary movements in relation to anticholinergics and levodopa therapy. Acta Neurol Scand 52: 158–160PubMedCrossRefGoogle Scholar
  9. Bleidner WE, Harmon TB, Hewes WE et al. (1965) Absorption, distribution and excretion of amantadine hydrochloride. J Pharmacol Exp Ther 150: 484–490PubMedGoogle Scholar
  10. Bradbury AJ, Kelly ME, Costall B, Naylor RJ, Jenne P, Marsden CD (1985) Benztropine inhibits toxicity of MPTP in mice. Lancet 1: 1444–1445PubMedCrossRefGoogle Scholar
  11. Bunney BS (1979) The electrophysiological pharmacology of midbrain dopaminergic systems. In: Horn AS, Korf J, Westernick BHC (eds) The neurobiology of dopamine. Academic, London, pp 417–452Google Scholar
  12. Burke RE (1986) The relative selectivity of anticholinergic drugs for the M1 and M2 muscarinic receptor subtypes. Movement Disorders 1: 135–144PubMedCrossRefGoogle Scholar
  13. Burke RE, Fahn S (1982) Pharmacokinetics of trihexyphenidyl after acute and chronic administration. Ann Neurol 12: 94Google Scholar
  14. Butzer NF, Silver D, Sahs AD (1975) Amantadine in Parkinson’s disease. Neurology (NY) 25: 603–606Google Scholar
  15. Casey DE (1978) Amantadine intoxication reversed by physostigmine. Engl J Med 298: 516Google Scholar
  16. Castaigne P, Laplane D, Dordain S (1972) Expérimentation clinique prolongée chez 50 parkinsoniens. Nouv Presse Med 1: 533–536PubMedGoogle Scholar
  17. Cook DG, Klawans HL (1985) Levodopa during pregnancy. Clin Neuropharmacol 8: 93–95PubMedCrossRefGoogle Scholar
  18. Corbin KB (1949) Trihexyphenidyl: evaluation of a new agent in treatment of parkinsonism. JAMA 141: 377–382CrossRefGoogle Scholar
  19. Coyle JT, Snyder SH (1969) Antiparkinsonism drugs: inhibition of dopamine uptake in the corpus striatum as a possible mechanism of action. Science 166: 899–901PubMedCrossRefGoogle Scholar
  20. Critchley E (1972) Levodopa and amantadine in the treatment of parkinsonism. Practitioner 208: 499–504PubMedGoogle Scholar
  21. Davies P, Maloney AJF (1976) Selective loss of central cholinergic neurones in Alzheimer’s disease. Lancet 2: 1403PubMedCrossRefGoogle Scholar
  22. Davies WL, Grunert RR, Haff RF, McGahen JW, Neumayer EM, Paulshock M, Watts JC, Wood TR, Hermann EC, Hoffmann CE (1964) Antiviral activity of 1-adamantanamine (amantadine). Science 144: 862–863PubMedCrossRefGoogle Scholar
  23. DeSmet Y, Ruberg M, Serdaru M, Dubois B, Lhermitte F, Agid Y (1982) Confusion dementia and anticholinergics in Parkinson’s disease. J Neurol Neurosurg Psychiatry 45: 1161–1164CrossRefGoogle Scholar
  24. Doshay LJ, Constable K (1949) Artane therapy for parkinsonism: a preliminary study of results of 117 cases. JAMA 140: 1317–1322CrossRefGoogle Scholar
  25. Duvoisin RC, (1967) Cholinergic-anticholinergic antagonism in parkinsonism. Arch Neurol 17: 124–136PubMedCrossRefGoogle Scholar
  26. Everett GM, Blockus LE, Sheppard IM (1956) Tremor induced by tremonine and its antagonism by antiparkinsonian drugs. Science 124: 79PubMedCrossRefGoogle Scholar
  27. Fabing HD, Zeligs MA (1941) Treatment of the post encephalitic parkinsonism syndrome with dessicated white wine extract of U.S.P. belladonna root. JAMA 117: 332–334CrossRefGoogle Scholar
  28. Fahn S (1982) Discussion. In: The management of Parkinson’s disease at different stages of the illness. Clin Neuropharm 5 (1): S9Google Scholar
  29. Fahn S, David E (1972) Orofacio-lingual dyskinesia due to anticholinergic medication, Trans Am Neurol Assoc 97: 277–279Google Scholar
  30. Fahn S, Isgreen W (1975) Long-term evaluation of amantadine and levodopa combination in parkinsonism by double blind crossover analysis. Neurology (NY) 25: 695–700Google Scholar
  31. Fahn S, Craddock G, Kumin G (1971) Acute toxic psychosis from suicidal overdosage of amantadine. Arch Neurol 25: 45–48PubMedCrossRefGoogle Scholar
  32. Farnebo L, Fuxe K, Hamberger B, Ljungdahl H (1970) Effect of some antiparkinsonian drugs on catecholamine neurons. J Pharm Pharmacol 22: 733–737PubMedCrossRefGoogle Scholar
  33. Fermaglich J, O’Doherthy S (1972) Effect of gastric motility on levodopa. Dis Nerv Syst 33: 624–625PubMedGoogle Scholar
  34. Friedman Z, Neumann E (1972) Benzhexol-induced blindness in Parkinson’s disease. Br Med J 1: 605PubMedCrossRefGoogle Scholar
  35. George R, Haslett WL, Jenden DJ (1966) The production of tremor by cholinergic drugs: central sites of action. Int J Neuropharmacol 5: 27–34PubMedCrossRefGoogle Scholar
  36. Goetz CG, Nausieda PA, Weiner WH, Klawans HL (1981) Practical guidelines for drug holidays in parkinsonian patients. Neurology (NY) 31: 641–642Google Scholar
  37. Grelak RP, Clark R, Stump JM, Vernier VG (1970) Amantadine-dopamine interaction. Science 169: 203–204PubMedCrossRefGoogle Scholar
  38. Hacohoen H, Gurtner B (1972) Clinical investigation into the effect of treatment with amantadine HCl in Parkinson’s disease, Schweiz Med Wochenschr 102: 583–586Google Scholar
  39. Hammer R, Giachetti A (1982) Muscarinic receptor subtypes: M1 and M2 biochemical and functional characterization. Life Sci 31: 2991–2998PubMedCrossRefGoogle Scholar
  40. Harper RW, Knothe BU (1973) Coloured lilliputian hallucinations with amantadine. Med J Aust 1: 444PubMedGoogle Scholar
  41. Himwish HE (1955) An analysis of the activating system including its use for screening antiparkinson drugs. Yale J Biol Med 28: 308Google Scholar
  42. Horadam VW, Sharp JG, Smilack JD, McAnalley BH, Garriott JC, Stephens MK, Prati RC, Brater DC (1981) Pharmacokinetics of amantadine hydrochloride in subjects with normal and impaired renal function. Ann Intern Med 94: 454–458PubMedGoogle Scholar
  43. Horrocks PM, Vicary DJ, Rees JE, Parkes JD, Marsden CD (1973) Anticholinergic withdrawal and benzhexol treatment in Parkinson’s disease. J Neurol Neurosurg Psychiatry 36: 936–941PubMedCrossRefGoogle Scholar
  44. Hughes RC, Polgar JG, Weightman D, Walton JN (1971) Levodopa in parkinsonism: the effects of withdrawal of anticholinergic drugs. Br Med J 2: 487–491PubMedCrossRefGoogle Scholar
  45. Hurtig HI (1980) Anticholinergics for Parkinson’s disease. Ann Neurol 7: 495PubMedCrossRefGoogle Scholar
  46. Iezzoni DG (1971) In: Birdwood GFB, Gilder SSB, Wink CAS (eds) Parkinson’s disease: a new approach to treatment. Academic, London, p 42Google Scholar
  47. Ing TS, Daugirdas JT, Soung LS, Klawans HL, Mahurkar SD, Hayashi JA, Geis WP, Hano JE (1979) Toxic effects of amantadine in patients with renal failure. Can Med Assoc J 120: 695–698PubMedGoogle Scholar
  48. Jain MK, Yen-Minwu N, Morgan TK et al. (1976) Phase transition in a lipid bilayer II. Influence of adamantane derivatives. Chem Phys Lipids 17: 71–78PubMedCrossRefGoogle Scholar
  49. Koelle GB (ed) (1963) Cholinesterases and anticholinesterase agents. Springer, Berlin Heidelberg New York, p 187 (Handbook of experimental pharmacology, vol 15 )Google Scholar
  50. Koller WC (1984) Disturbance of recent memory functions in parkinsonian patients on anticholinergic therapy. Cortex 20: 307–311PubMedGoogle Scholar
  51. Koller WC (1986) Pharmacologic treatment of parkinsonian tremor. Arch Neurol 43: 126–127PubMedCrossRefGoogle Scholar
  52. Lang AE (1984) Treatment of Parkinson’s disease with agents other than levodopa and dopamine agonists: controversies and new approaches. Can J Neurol Sci 11: 210–220PubMedGoogle Scholar
  53. Liu P, Cheng PJ, Ing TS, Daugirdas JT, Jeevanandhan R, Soung LS, Galinis S (1984) In vitro binding of amantadine to plasma proteins. Clin Neuropharmacol 7: 159–151CrossRefGoogle Scholar
  54. Marsden CD (1976) Advances in the management of Parkinson’s disease, Scott Med J 21: 139–148PubMedGoogle Scholar
  55. Marshall J, Schnieden H (1966) Effects of adrenaline, noradrenaline, atropine and nicotine on some types of human tremor. J Neurol Neurosurg Psychiatry 29: 214–218PubMedCrossRefGoogle Scholar
  56. Nashold BS (1959) Cholinergic stimulation of globus pallidus in man. Proc Soc Exp Biol Med 101: 68PubMedGoogle Scholar
  57. Nastuck WL, Su PC, Doubilet P (1976) Anticholinergic and membrane activities of amantadine in neuromuscular transmission. Nature 264: 76–79CrossRefGoogle Scholar
  58. Nora JJ, Nora AH, Way GL (1975) Cardiovascular maldevelopment associated with maternal exposure to amantadine. Lancet 2: 607PubMedCrossRefGoogle Scholar
  59. Ordenstein L (1867) Sur la paralysie agitante et la sclérose en plaque generalisé. Martinet, ParisGoogle Scholar
  60. Pacifici GM, Nardin M, Ferrari P, Latini R, Freschi C, Morselli PC (1976) Effect of amantadine on drug-induced parkinsonism: relationship between plasma levels and effect. Br J Clin Pharmacol 3: 883–889PubMedGoogle Scholar
  61. Parkes JD, Zilkha KJ, Calver DM, Knill-Jones RP (1970) Controlled trial of amantadine hydrochloride in Parkinson’s disease. Lancet 1: 259–262PubMedCrossRefGoogle Scholar
  62. Parkes JD, Curzon G, Knott PJ, Tatersall R, Baxter RCH, Knill-Jones RP, Marsden CD, Vollum D (1971a) Treatment of Parkinson’s disease with amantadine and levodopa. Lancet 1: 1083–1086PubMedCrossRefGoogle Scholar
  63. Parkes JD, Knill-Jones RP, Clements PJ (1971b) L-Dopa and amantadine hydrochloride in extrapyramidal disorders. Postgrad Med J 47: 116–119PubMedCrossRefGoogle Scholar
  64. Parkes JD, Zilkha KJ, Knill-Jones RP, Clements PJ, Baxter R (1971c) L-Dopa and amantadine hydrochloride in Parkinson’s disease. Int J Clin Pharmacol Ther Toxicol 4: 356–360Google Scholar
  65. Parkes JD, Baxter RC, Galbraith A, Marsden CD, Rees JE (1973) Amantadine treatment in Parkinson’s disease. Adv Neurol 3: 105–114Google Scholar
  66. Parkes JD, Baxter RC, Marsden CD, Rees JE (1974) Comparative trial of benzhexol, amantadine and levodopa in the treatment of Parkinson’s disease. J Neurol Neurosurg Psychiatry 37: 422–425PubMedCrossRefGoogle Scholar
  67. Pearce J (1971) Mechanism of action of amantadine. Br Med J 3: 529PubMedCrossRefGoogle Scholar
  68. Pileblad E, Carlsson A (1985) Catecholamine-uptake inhibitors prevent the neurotoxicity of l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) in mouse brain. Neuropharmacology 24: 689–592PubMedCrossRefGoogle Scholar
  69. Pollock M, Jorgenson PB (1972) Combined L-Dopa and amantadine in parkinsonism. Austr NZ J Med 3: 252–255CrossRefGoogle Scholar
  70. Postma JU, Van Tilburg W (1975) Visual hallucinations and delerium during treatment with amantadine (Symmetrel). J Am Geriatr Soc 23: 212–215PubMedGoogle Scholar
  71. Price JC, Merritt HH (1941) The treatment of parkinsonism: results obtained with wine of Bulgarian belladonna and alkaloids of U.S.P. belladonna. JAMA 117: 335–337CrossRefGoogle Scholar
  72. Pycock C, Milson JA, Tarsy D et al. (1976) The effects of blocking catecholamine uptake on amphetamine-induced circling behaviour in mice with unilateral destruction of striatal dopaminergic nerve terminals. J Pharm Pharmacol 28: 530–532PubMedCrossRefGoogle Scholar
  73. Quinn NP (1984) Antiparkinsonian drugs today. Drugs 28: 236–262PubMedCrossRefGoogle Scholar
  74. Randrup A, Mogilnicka E (1976) Spectrum of pharmacological actions on brain dopamine. Indications for development of new psychoactive drugs. Discussion of amantadines as examples of new drugs with special actions on dopamine systems. Pol J Pharmacol Pharm 28: 551–556PubMedGoogle Scholar
  75. Rao NS, Pearce J (1971) Amantadine in parkinsonism: an extended prospective trial. Practitioner 206: 241–245PubMedGoogle Scholar
  76. Ruberg M, Ploska A, Javoy-Agid F, Agid Y (1982) Muscarinic binding and choline acetyltransferase activity in parkinsonian subjects with reference to dementia. Brain Res 232: 129–139PubMedCrossRefGoogle Scholar
  77. Sacks OW, Schwartz WF, Messeloff CR (1971) Interactions of L-dopa and amantadine in parkinsonism. Clin Pharmacol Ther 12. (1): 301Google Scholar
  78. Sadeh M, Braham J, Modan M (1982) Effects of anticholinergic drugs on memory in Parkinson’s disease. Arch Neurol 39: 666–667PubMedCrossRefGoogle Scholar
  79. Schwab RS (1961) Symptomatology and medical treatment of Parkinson’s disease. Int J Neurol 2: 61–75PubMedGoogle Scholar
  80. Schwab RS, England AC, Poskanzer DC, Young RR (1969) Amantadine in the treatment of Parkinson’s disease. JAMA 208: 1168–1170.PubMedCrossRefGoogle Scholar
  81. Schwab RS, Poskanzer DC, England AC, Young RR (1972) Amantadine in Parkinson’s disease: review of more than two years’ experience. JAMA 222: 792–795PubMedCrossRefGoogle Scholar
  82. Schwab RS, Chafetz ME (1955) Kemadrin in the treatment of parkinsonism. Neurology (Minneap) 5: 273–277Google Scholar
  83. Schwab RS, Leigh D (1949) Parpanit in the treatment of Parkinson’s disease. JAMA 139: 629–634CrossRefGoogle Scholar
  84. Shannon KM, Goetz CG, Carroll VS, Tanner CM, Klawans HL (1986). Amantadine and motoric fluctiations in chronic Parkinson’s disease. Neurology 36 (Suppl 1): 182Google Scholar
  85. Stone TW (1976) Responses of neurons in the cerebral cortex and caudate nucleus to amantadine, amphetamine and dopamine. Br J Pharmacol 1: 101–110Google Scholar
  86. Stomberg U, Svensson TM (1971) Further studies on the mode of action of amantadine. Acta Pharmacol Toxicol (Copenh) 30: 161–171CrossRefGoogle Scholar
  87. Strang RR (1965) Kemadrin in the treatment of parkinsonism: a double blind and one year follow-up study. Curr Med Drugs 5: 27–32Google Scholar
  88. Syndulko K, Gilden ER, Hansch EC, Potvin AR, Tourtellotte WW, Potvin JH (1981) Decreased verbal memory associated with anticholinergic treatment in Parkinson’s disease. Int J Neurosci 14: 61–66PubMedCrossRefGoogle Scholar
  89. Tasker RR, Kertesz A (1965) The physiology of tremorine-induced tremor. J Neurosurg 22: 449–456PubMedCrossRefGoogle Scholar
  90. Tilley JW, Kramer MJ (1981) Aminoadamantane derivaties. Prog Med Chem 18: 1–44PubMedCrossRefGoogle Scholar
  91. Timberlake WH, Vance MA (1978) Four years treatment of patients with parkinsonism using amantadine alone or with levodopa. Ann Neurol 3: 119–128PubMedCrossRefGoogle Scholar
  92. Vollum D, Parkes JD, Doyle D (1971) Livedo reticularis during amantadine treatment. Br Med J 2: 627–628PubMedCrossRefGoogle Scholar
  93. Von Voigtlander PF, Moore KE (1971) Dopamine: release from the brain in vivo by amantadine. Science 174: 408–410CrossRefGoogle Scholar
  94. Walker JE, Potvin A, Tourtelotte W, Albers J, Repa B, Henderson W, Snyder D (1972) Amantadine and levodopa in the treatment of Parkinson’s disease. Clin Pharmacol Ther 13: 28–36PubMedGoogle Scholar
  95. Weintraub MI, Van Woert MH (1971) Reversal by levodopa of cholinergic hypersensitivity in Parkinson’s disease. N Engl J Med 284: 412–415PubMedCrossRefGoogle Scholar
  96. Whitehouse PJ, Price DL, Clarke AW, Coyle JT, DeLong MR (1981) Alzheimer’s disease: evidence for selective cholinergic neurones in the nucleus basalis. Ann Neurol 13: 243–248CrossRefGoogle Scholar
  97. Whitehouse PJ, Hedreen JC, White CL, Price DL (1983) Basal forebrain neurones in the dementia of Parkinson’s disease. Ann Neurol 13: 243–248PubMedCrossRefGoogle Scholar
  98. Wilson TW, Rajput AH (1983) Amantadine-Dyazide interaction. Can Med Assoc J 129: 974–975PubMedGoogle Scholar
  99. Yahr MD, Clough CG, Bergmann KJ (1982) Cholinergic and dopaminergic mechanisms in Parkinson’s disease after long term levodopa administration. Lancet 2: 709–710PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1989

Authors and Affiliations

  • A. E. Lang
  • R. D. G. Blair

There are no affiliations available

Personalised recommendations